The safety, tolerability, and pharmacokinetics of PNU-96391, an orally active weak dopamine D2 receptor antagonist with modulatory properties of central dopaminergic function, was characterized. Fifty-three healthy normal volunteers were enrolled in this randomized, double-blinded, placebo-controlled, single-dose study. Subjects were assigned to single oral doses of placebo and 1, 3, 10, 30, 100, 150, and 200 mg PNU-96391. Safety and tolerability were assessed using telemetry, Holter monitoring, surface ECG, vital signs, safety laboratories, and adverse event reports. Pharmacokinetic parameters were determined by model-independent techniques. Adverse events were infrequent, of mild to moderate intensity, and in the dose range of 1 to 150 mg. Dose escalation was stopped at 200 mg because of severe nausea, dizziness, lightheadedness, and tachycardia. Besides the increase in heart rate, no other drug-related effects on vital signs were observed. Safety laboratory measurements were not significantly changed. Evidence of drug activity was demonstrated by a dose-dependent elevation in serum prolactin. PNU-96391 was rapidly absorbed, with maximum concentrations achieved between 0.5 and 4 hours in all subjects. The half-life of the drug was short (2 to 6 h). The main metabolite, PNU-100014, was rapidly formed, with a t(max) ranging from 1 to 6 hours. Peak levels of the metabolite are approximately half of the parent drug, and the half-life is slightly longer (4 to 10 h). Increases in dose resulted in linear increases in exposure for both PNU-96391 and PNU-100014. Hence, PNU-96391 was well tolerated at doses ranging from 1 to 150 mg.